Clinical, pathologic, and experimental studies support an important role for inflammation in vascular injury and repair states such as atherosclerosis or restenosis following angioplasty. The injury response is a complex process, which involves the participation of both immune and non-immune cells. With respect to immune cells, accumulating evidence supports a central role for the monocyte. The broad objectives of our study are to understand the molecular mechanisms governing monocyte development and function in vascular injury and repair states. We have identified a member of the Kruppel-like family of zinc finger class of transcription factors termed KLF4, which is highly expressed, in human monocytes. Amongst hematopoietic cell lines and primary bone marrrow derived cells, KLF4 expression is limited to cells of the monocytic lineage. Retroviral overexpression of KLF4 in a promyelocytic cell line induces the morphologic and genetic characteristics of a monocyte. In addition, KLF4 over expression promotes characteristic monocyte functions such as adhesion and phagocytosis. These observations serve as the basis for the central hypothesis of this proposal that KLF4 regulates monocyte development and function in vascular injury and repair states. The studies outlined in this proposal will (1) determine the structural basis for KLF4 ability to regulate monocyte target genes, (2) determine the mechanism(s) underlying KLF4's ability to promote monocyte differentiation (3) place KLF4 within the trancriptional hierarchy governing monocyte differentiation and (4) determine the effect of KLF4 deficiency on monocyte function and development of experimental atherosclerosis. These studies should provide important insights regarding the role of KLF4 in monocyte biology and function. The results of these investigations are of considerable scientific interest and may serve as the basis of novel therapeutic strategies to modulate the blood vessel's response to injury.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Pathology A Study Section (PTHA)
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Srinivas, Pothur R
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Brigham and Women's Hospital
United States
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